MicroRNA-195 Suppresses Angiogenesis and Metastasis of Hepatocellular Carcinoma by Inhibiting the Expression of VEGF, VAV2, and CDC42
MicroRNA-195 Suppresses Angiogenesis and Metastasis of Hepatocellular Carcinoma by Inhibiting the Expression of VEGF, VAV2, and CDC42
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MicroRNA-195通过抑制VEGF、VAV2和CDC42的表达抑制肝细胞癌的血管生成和转移
DOI：
10.1002/hep.26373
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发表时间：
2013-08-01
期刊：
影响因子：
13.5
通讯作者：
Zhuang, Shi-Mei
中科院分区：
文献类型：
--
作者：
Wang, Ruizhi;Zhao, Na;Zhuang, Shi-Mei
肝细胞癌（HCC）的特点是活跃的血管生成和转移，这是快速复发和生存率低的原因。miR-195在HCC组织中表达频繁下调。在这项研究中，miR-195在HCC血管生成和转移中的作用通过体外毛细管形成和transwell测定、体内原位异种移植小鼠模型和人HCC标本进行了研究。HCC组织中miR-195的减少与血管生成增加、转移和无复发生存率降低显著相关。体外模型的功能获得和功能丧失研究均显示，miR-195不仅抑制HCC细胞促进内皮细胞迁移和毛细血管形成的能力，而且直接抑制HCC细胞迁移和侵入细胞外基质凝胶的能力。基于小鼠模型，我们发现miR-195的诱导表达显著降低了异种移植肿瘤中的微血管密度，并抑制了肝内和肺转移。随后的研究发现，miR-195直接抑制促血管生成因子血管内皮生长因子（VEGF）和促转移因子VAV 2和CDC 42的表达。这些miR-195靶分子的敲除表型模拟了miR-195恢复的作用，而这些靶分子的过表达拮抗了miR-195的功能。此外，我们发现miR-195下调导致肿瘤微环境中VEGF水平增强，随后激活内皮细胞中的VEGF受体2信号传导，从而促进血管生成。此外，miR-195下调导致VAV 2和CDC 42表达增加，这刺激了VAV 2/Rac 1/CDC 42信号传导和板状伪足形成，从而促进HCC细胞的转移。结论：miR-195表达异常促进了HCC的血管生成和转移。恢复miR-195的表达可能是HCC治疗的一个有希望的策略。（肝病学2013;58：642-653）
Hepatocellular carcinoma (HCC) is characterized by active angiogenesis and metastasis, which account for rapid recurrence and poor survival. There is frequent down-regulation of miR-195 expression in HCC tissues. In this study, the role of miR-195 in HCC angiogenesis and metastasis was investigated with in vitro capillary tube formation and transwell assays, in vivo orthotopic xenograft mouse models, and human HCC specimens. Reduction of miR-195 in HCC tissues was significantly associated with increased angiogenesis, metastasis, and worse recurrence-free survival. Both gain-of-function and loss-of-function studies of in vitro models revealed that miR-195 not only suppressed the ability of HCC cells to promote the migration and capillary tube formation of endothelial cells but also directly repressed the abilities of HCC cells to migrate and invade extracellular matrix gel. Based on mouse models, we found that the induced expression of miR-195 dramatically reduced microvessel densities in xenograft tumors and repressed both intrahepatic and pulmonary metastasis. Subsequent investigations disclosed that miR-195 directly inhibited the expression of the proangiogenic factor vascular endothelial growth factor (VEGF) and the prometastatic factors VAV2 and CDC42. Knockdown of these target molecules of miR-195 phenocopied the effects of miR-195 restoration, whereas overexpression of these targets antagonized the function of miR-195. Furthermore, we revealed that miR-195 down-regulation resulted in enhanced VEGF levels in the tumor microenvironment, which subsequently activated VEGF receptor 2 signaling in endothelial cells and thereby promoted angiogenesis. Additionally, miR-195 down-regulation led to increases in VAV2 and CDC42 expression, which stimulated VAV2/Rac1/CDC42 signaling and lamellipodia formation and thereby facilitated the metastasis of HCC cells. Conclusion: miR-195 deregulation contributes to angiogenesis and metastasis in HCC. The restoration of miR-195 expression may be a promising strategy for HCC therapy. (Hepatology 2013;58:642-653)